Langenbeck's Archives of Surgery

, Volume 394, Issue 1, pp 159–169 | Cite as

Pancreaticobiliary maljunction and carcinogenesis to biliary and pancreatic malignancy

  • Takahiko Funabiki
  • Toshiki Matsubara
  • Shuichi Miyakawa
  • Shin Ishihara
New Surgical Horizons



It is widely accepted that congenital choledochal cyst is associated with pancreaticobiliary maljunction (PBM). But, PBM is an independent disease entity from choledochal cyst. PBM is synonymous with “abnormal junction of the pancreaticobiliary ductal system”, “anomalous arrangement of pancreaticobiliary ducts”, “anomalous union of bilio-pancreatic ducts”, etc. Cases with PBM not associated with biliary duct dilatation are often found, and these cases are frequently complicated gallbladder cancer. The Japanese Study Group of Pancreaticobiliary Maljunction was started in 1983, and defined diagnostic criteria and nationwide registration system of PBM cases was started. PBM is defined as a union of the pancreatic and biliary ducts which is located outside the duodenal wall. Bile and pancreatic juice reflux and regurgitate mutually.

Biliary carcinogenesis

The most bothersome problem is biliary carcinogenesis. Gallbladder cancers arise in 14.8% and bile duct cancers arise in 4.9%. The incidence of the gallbladder carcinoma of PBM without bile duct dilatation is 36.1%. Many investigators have tried to clarify the carcinogenic process, from various aspects. The biliary epithelia are injured by harmful substances, and in the course of repair, multiple alterations of oncogenes and tumor suppressor genes are followed, and they lead to carcinoma through multistage interaction. In the biliary epithelia of PBM, incidence and degree of hyperplasia are characteristic. K-ras gene mutations are observed in the cancerous as well as noncancerous lesions of biliary tract of PBM patients. Mutations of p53 gene and overexpression of p53 protein are also found in the cancerous and noncancerous lesions. These changes are called “hyperplasia–carcinoma sequence”.


Total excision of the extrahepatic bile duct with gallbladder followed by hepaticojejunostomy, Roux-en-Y, or end-to-side hepaticoduodenostomy are treatment of choice, even for cases with not dilated bile duct, because the incidence of cancer in the nondilated bile duct is not negligible, and genetic changes are seen in a nondilated bile duct.


Pancreaticobiliary maljunction Gallbladder cancer Bile duct cancer k-ras gene mutation p53 gene mutation Bile duct dilatation 


  1. 1.
    Kelly TR, Schlueter TM (1964) Choledochal cyst with coexistent carcinoma of the pancreas. Am Surg 30:209–212PubMedGoogle Scholar
  2. 2.
    Komi N, Kunitomo K, Tamura T, Udaka H, Miyoshi Y, Takehara H (1984) Nationwide survey of cases of choledochal cyst: analysis of coexistent anomalies, complications and surgical treatment in 645 cases. Surg Gastroenterol 3:69–73PubMedGoogle Scholar
  3. 3.
    Kozumi K, Kodama T (1916) A case of cystic dilatation of the common bile duct and etiology of the disease (in Japanese). Tokyo Med J 30:1413–1423Google Scholar
  4. 4.
    Babbitt DP (1969) Congenital choledochal cysts: new etiological concept based on anomalous relationships of the common bile duct and pancreatic bulb. Ann Surg (Paris) 12:231–240Google Scholar
  5. 5.
    Hasumi A, Matsui H, Sugioka A, Uyama I, Komori Y, Fujita J, Aoki H (2000) Precancerous conditions of biliary tract cancer in patients with pancreaticobiliary maljunction: reappraisal of nationwide survey in Japan. J Hepatobiliary Pancreat Surg 7:551–555PubMedCrossRefGoogle Scholar
  6. 6.
    Yamao K, Mizutani S, Nakazawa S, Inui K, Kanemaki N, Miyoshi H, Segawa K, Zenda H, Kato T (1996) Prospective study of the detection of anomalous connection of pancreatobiliary ducts during routine medical examinations. Hepatogastroenterology 43:1238–1245PubMedGoogle Scholar
  7. 7.
    Mori K, Akimoto R, Kanno M, Kamata T, Hirono Y, Matsumura A (1999) Anomalous union of the pancreaticobiliary ductal system without dilatation of the common bile duct or tumor: cases report and literature review. Hepatogastroenterology 46:142–148PubMedGoogle Scholar
  8. 8.
    Yamauchi S, Koga A, Matsumoto S, Tanaka M, Nakayama F (1987) Anomalous junction of pancreaticobiliary duct without congenital choledochal cyst: a possible risk factor for gallbladder cancer. Am J Gastroenterol 82:20–24PubMedGoogle Scholar
  9. 9.
    Chang LY, Wang HP, Wu MS, Hang HT, Wang HH, Lin CC, Lin JT (1998) Anomalous pancreaticobiliary ductal union—an etiologic association of gallbladder cancer and adenomyomatosis. Hepatogastroenterology 45:2016–2019PubMedGoogle Scholar
  10. 10.
    Tuech JJ, Pessaux P, Aube C, Regent N, Cervi C, Bergamaschi R, Aunaud JP (2000) Cancer of the gallbladder associated with pancreaticobiliary maljunction without bile duct dilatation in a European patient. J Hepatobiliary Pancreat Surg 7:336–338PubMedCrossRefGoogle Scholar
  11. 11.
    Todani T, Arima E, Eto T, Funabiki T, Kakita A, Kimura K, Ohi R, Oi I, Matsumoto Y, Miyano T, Suda K, Takahara H, (JSPBM Committee for diagnostic criteria) (1994) Diagnostic criteria of pancreaticobiliary maljunction. J Hepatobiliary Pancreat Surg 1:219–221CrossRefGoogle Scholar
  12. 12.
    Adham M, Valette PJ, Partensky C (2005) Pancreaticobiliary maljunction without choledochal dilatation associated with gallbladder cancer: report of 2 European cases. Surgery 138:961PubMedCrossRefGoogle Scholar
  13. 13.
    Dowdy GS, Waldron GW, Brown WD (1962) Surgical anatomy of the pancreaticobiliary ductal system. Arch Surg 84:229–246PubMedGoogle Scholar
  14. 14.
    Matsumoto Y, Fujii H Itakura J, Matsuda M, Yang Y Nobukawa B, Suda K (2003) Pancreaticobiliary maljunction: pathophysiological and clinical aspects and the impact on biliary carcinogenesis. Langenbeck’s Arch Surg 388:122–131Google Scholar
  15. 15.
    Kamisawa T, Funata N, Hayashi Y, Egawa N, Nakajima H, Tsuruta K, Okamoto A, Yamaguchi T (2004) Pathologic changes in the non-carcinomatous epithelium of the gallbladder in patients with a relatively long common channel. Gastrointest Endosc 60:56–60PubMedCrossRefGoogle Scholar
  16. 16.
    Irwin ST, Morison JE (1944) Congenital cyst of the common bile duct containing stones and undergoing cancerous change. Br J Surg 33:261–270Google Scholar
  17. 17.
    Todani T, Watanabe Y, Toki A, Urushihara N (1987) Carcinoma related to choledochal cysts with internal drainage operations. Surg Gynecol Obstet 164:61–64PubMedGoogle Scholar
  18. 18.
    Rossi RL, Silverman ML, Braasch JW, Munson JL, Remine SG (1987) Carcinomas arising in cystic conditions of the bile ducts: a clinical and pathologic study. Ann Surg 205:377–384PubMedCrossRefGoogle Scholar
  19. 19.
    Todani T, Watanabe Y, Fujii H, Toki, Uemura S, Koike Y, Inoue T (1985) Carcinoma arising from the bile duct in choledochal cyst and anomalous arrangement of the pancreaticobiliary ductal union. Tan to Sui (Biliary Tract Pancreas, in Japanese) 6:525–535Google Scholar
  20. 20.
    Okamoto A, Tsuruta K, Matsumoto G, Takahashi T, Kamisawa T, Egawa N, Funata N (2003) Papillary carcinoma of the extrahepatic bile duct: characteristic features and implications in surgical treatment. J Am Coll Surg 196:394–401PubMedCrossRefGoogle Scholar
  21. 21.
    Tashiro S, Imaizumi T, Ohkawa H, Okada A, Katoh T, Kawaharada Y, Shimada H, Takamatsu H, Miyake H, Todani T (2003) Pancreaticobiliary maljunction: retrospective and nationwide survey in Japan. J Hepatobiliary Pancreat Surg 10:345–351PubMedCrossRefGoogle Scholar
  22. 22.
    Tanaka S, Kubota M, Yagi M, Okuyama N, Ohtani M, Yamazaki S, Hirayama Y, Kurosaki I, Hatakeyama K (2006) An 11-year-old male patient demonstrating cholangiocarcinoma associated with congenital biliary dilatation. J Pediatr Surg 41:E15–E19PubMedCrossRefGoogle Scholar
  23. 23.
    Iwai N, Deguchi E, Yanagihara J, Iwai M, Matsuo H, Todo S, Imashuku S (1990) Cancer arising in a choledochal cyst in a 12-year-old girl. J Pediatr Surg 25:1261–1263PubMedCrossRefGoogle Scholar
  24. 24.
    Ohuchida J, Chijiiwa K, Hiyoshi M, Kobayashi K, Konomi H, Tanaka M (2006) Long-term results of treatment of pancreaticobiliary maljunction without bile duct dilatation. Arch Surg 141:1066–1070PubMedCrossRefGoogle Scholar
  25. 25.
    Ichikawa Y, Kamiyama M, Sekido H, Ishikawa T, Miura Y, Kamiya N, Morita T, Shimada H (2004) Telomerase activity and Bcl-2 expression in gallbladders of pancreaticobiliary maljunction patients: a preliminary study. J Hepatobiliary Pancreat Surg 11:34–39PubMedCrossRefGoogle Scholar
  26. 26.
    Seki M, Yanagisawa A, Ninomiya E, Ninomiya Y, Ohta H, Saiura A, Yamamoto J, Yamaguchi T, Agura A, Yamada K, Takano K, Fujita R, Ikeda M, Sasaki K, Kato Y (2005) Clinicopathology of pancreaticobiliary maljunction: relationship between alterations in background biliary epithelium and neoplastic development. J Hepatobiliary Pancreat Surg 12:254–262PubMedCrossRefGoogle Scholar
  27. 27.
    Fieber SS, Nance FC (1997) Choledochal cyst and neoplasm: a comprehensive review of 106 cases and presentation of two original cases. Am Surg 63:982–987PubMedGoogle Scholar
  28. 28.
    Funabiki T (2000) Pancreaticobiliary Maljunction—focused on biliary carcinogenesis (in Japanese). Jpn J Gastroenterol Surg 33:261–270Google Scholar
  29. 29.
    Okamura K, Hayakawa H, Kuze M, Takahashi H, Kosaka A, Mizumoto R, Katsuta K (2000) Triple carcinomas of the biliary tract associated with congenital choledochal dilatation and pancreaticobiliary maljunction. J Gastroenterol 35:465–471PubMedCrossRefGoogle Scholar
  30. 30.
    Takayashiki T, Miyazaki M, Kato A, Ito H, Nakagawa K, Ambiru S, Shimizu H, Furuya S, Nakajima N (2002) Double cancer of gallbladder and bile duct associated with anomalous junction of the pancreaticobiliary ductal system. Hepatogastroenterology 49:109–112PubMedGoogle Scholar
  31. 31.
    Marugame T, Matsuda T, Kamo K, Katanoda K, Ajiki W, Sobue T, Japanese cancer surveillance research group (2007) Cancer incidence rates in Japan in 2001 based on the data from 10 population-based cancer registries. Jpn J Clin Oncol 37:884–891PubMedCrossRefGoogle Scholar
  32. 32.
    Binks JB, Pauline GJ (1970) Choledochal cyst and carcinoma of the pancreas in a boy of fifteen years. Aust NZ J Surg 40:42–44CrossRefGoogle Scholar
  33. 33.
    Tsuchida A, Kasuya K, Endo M, Saito H, Inoue K, Nagae I, Aoki T, Koyanagi Y (2003) High risk of bile duct carcinogenesis after primary resection of a congenital biliary dilatation. Oncol Rep 10:1183–1187PubMedGoogle Scholar
  34. 34.
    Yamashiro Y, Miyano T, Suruga K, Shimomura H, Suda K, Matsumoto M, Nittono H (1984) Experimental study of the pathogenesis of choledochal cyst and pancreatitis, with special reference to the role of bile acids and pancreatic enzymes in the anomalous choledocho-pancreatico ductal junction. J Pediatr Gastroenterol Nutr 3:721–727PubMedCrossRefGoogle Scholar
  35. 35.
    Kato T, Matsuda K, Kayaba H, Enomoto S, Hebiguchi T, Koyama K, Hachiya N, Takizawa Y (1989) Pathology of anomalous junction of the pancreaticobiliary ductal system: mutagenicity of the contents of the biliary tract and nuclear atypia of the biliary epithelium. Keio J Med 38:167–176PubMedGoogle Scholar
  36. 36.
    Shimada K, Yanagisawa J, Nakayama F (1991) Increased lysophosphatidylcholine and pancreatic enzyme content in bile of patients with anomalous pancreaticobiliary ductal system. Hepatology 13:438–444PubMedGoogle Scholar
  37. 37.
    Mizuno M, Kato T, Koyama K (1996) An analysis of mutagens in the contents of the biliary tract in pancreaticobiliary maljunction. Surg Today 26:597–602 (1996)PubMedCrossRefGoogle Scholar
  38. 38.
    Takabayashi A, Soloway RD (1981) The role of bile acids in the pathogenesis of carcinoma of the gallbladder. Kitano Hospital J Med 26:153–160Google Scholar
  39. 39.
    Reveille RM, VanStiegmann G, Everson GT (1990) Increased secondary bile acids in a choledochal cyst. Gastroenterology 99:525–527PubMedGoogle Scholar
  40. 40.
    Funabiki T, Sugiue K, Matsubara T, Amano H, Ochiai M (1991) Bile acids and biliary carcinoma in pancreaticobiliary maljunction. Keio J Med. 40:118–122PubMedGoogle Scholar
  41. 41.
    Qian D, Kinouchi T, Kunitomo K, Kataoka K, Matin MA, Akimoto S, Komi N, Ohnishi Y (1993) Mutagenicity of the bile of dogs with an experimental model of an anomalous arrangement of the pancreaticobiliary duct. Carcinogenesis 14:743–747PubMedCrossRefGoogle Scholar
  42. 42.
    Fortner JG (1957) An appraisal of the pathogenesis of primary carcinoma of the extrahepatic biliary tract. Surgery 43:563–571Google Scholar
  43. 43.
    Shimada K, Chijiiwa K, Yanagisawa J, Nakayama F (1993) Biliary bile acids in the gallbladder and the common bile duct of patients with anomalous pancreaticobiliary ductal system. J Gastroenterol Hepatol 8:138–141PubMedCrossRefGoogle Scholar
  44. 44.
    Matsubara T, Tsuji A, Miyama H, Yamaguchi H, Funabiki T (1995) Mutagenicity of bile and pancreatic juice from patients with pancreatico-biliary maljunction. Hepatogastroenterol 42:113–116Google Scholar
  45. 45.
    Hanada K, Itoh M, Fujii K, Tsuchida A, Hirata M, Ishimaru S, Iwao T, Eguchi N, Kajiyama G (1996) Pathology and cellular kinetics of gallbladder with an anomalous junction of pancreaticobiliary duct. Am J Gastroenterol 91:1007–1011PubMedGoogle Scholar
  46. 46.
    Tanno S, Obara T, Fujii T, Mizukami Y, Shudo R, Nishino N, Ura H, Klein-Szanto AJ, Kohgo Y (1998) Proliferative potential and k-ras mutation in epithelial hyperplasia of the gallbladder in patients with anomalous pancreaticobiliary ductal union. Cancer 83:267–275PubMedCrossRefGoogle Scholar
  47. 47.
    Tsuchida A, Itoi T, Aoki T, Koyanagi Y (2003) Carcinogenetic process in gallbladder mucosa with pancreaticobiliary maljunction (Review). Oncol Rep 10:1693–1699PubMedGoogle Scholar
  48. 48.
    Tokiwa K, Iwai N, Nakamura K, Okuzumi J, Yamane T, Takahashi T (1991) Gallbladder mucosa ornithine decarboxylase activity is increased in patients with anomalous arrangement of the pancreaticobiliary duct. Cancer 69:2440–2443CrossRefGoogle Scholar
  49. 49.
    Hara H, Morita S, Ishibashi T, Sako S, Dohi T, Otani M, Iwamoto M, Inoue H, Tanigawa N (2002) Studies on biliary tract carcinoma in the case with pancreaticobiliary maljunction. Hepatogastroenterol 49:104–108Google Scholar
  50. 50.
    Isozaki H, Okajima K, Hara H, Sako S, Mabuchi H (1997) Proliferating cell nuclear antigen expression in the gallbladder with pancreaticobiliary maljunction. J Surg Oncol 65:46–49PubMedCrossRefGoogle Scholar
  51. 51.
    Yamato T, Kurumaya H, Ohma K, Yamamichi N, Watanabe Y, Harada K, Sasaki M, Nakamura Y (1999) Frequent expression of mucin core protein MUC1 in non-neoplastic gallbladder mucosa from patients with pancreaticobiliary maljunction. Liver 19:281–287PubMedCrossRefGoogle Scholar
  52. 52.
    Tsuchida A, Nagakawa Y, Kasuya K, Itoi T, Endo M, Ozawa T, Aoki T, Koyanagi Y (2003) Immunohistochemical analysis of cyclooxygenase-2 and vascular endothelial growth factor in pancreaticobiliary maljunction. Oncol Rep 10:339–343PubMedGoogle Scholar
  53. 53.
    Otani K, Shimizu S, Chijiiwa K, Yamaguchi K, Noshiro H, Tanaka M (2001) Immunohistochemical detection of 8-hydroxy-2′-deoxyguanosine in gallbladder epithelium of patients with pancreaticobiliary maljunction. Eur J Gastroenterol Hepatol 13:1363–1369PubMedCrossRefGoogle Scholar
  54. 54.
    Nagai M, Watanabe M, Iwase T, Yamao K, Isaji S (2002) Clinical and genetic analysis of noncancerous and cancerous biliary epithelium in patients with pancreaticobiliary maljunction. World J Surg 26:91–98PubMedCrossRefGoogle Scholar
  55. 55.
    Miura Y, Ichikawa Y, Ishikawa T, Sekido H, Nakano A, Mitsuhashi M, Shimada H (1998) The elevated mRNA content as a potential indicator of precancerous states of the gallbladder mucosa in patients with pancreaticobiliary maljunction. Oncol Rep 5:845–851PubMedGoogle Scholar
  56. 56.
    Itoi T, Watanabe H, Yoshikawa T, Ajioka Y, Nishikura K, Saito T (1996) K-ras mutations in gallbladder carcinomas in patients with anomalous arrangement of the pancreaticobiliary duct. Acta Med Biol 44:71–77Google Scholar
  57. 57.
    Chao TC, Wang CS, Jan YY, Chen HM, Chen MF (1999) Carcinogenesis in the biliary system associated with APDJ. J Hepatobiliary Pancreat Surg 6:218–222PubMedCrossRefGoogle Scholar
  58. 58.
    Matsubara T, Sakurai Y, Sasayama Y, Hori H, Ochiai M, Funabiki T (1996) K-ras point mutations in cancerous and noncancerous biliary epithelium in patients with pancreaticobiliary maljunction. Cancer 77:1752–1757PubMedGoogle Scholar
  59. 59.
    Funabiki T, Matsubara T, Ochiai M, Marugami Y, Sakurai Y, Hasegawa S, Imazu H (1997) Biliary carcinogenesis in pancreaticobiliary maljunction. J Hepatobiliary Pancreat Surg 4:405–411CrossRefGoogle Scholar
  60. 60.
    Matsubara T, Sakurai Y, Zhi L-Z, Miura H, Ochiai M, Funabiki T (2002) K-ras and p-53 gene mutations in noncancerous biliary lesions of patients with pancreatico biliary maljunction. J Hepatobiliary Pancreat Surg 9:312–321PubMedCrossRefGoogle Scholar
  61. 61.
    Hanada K, Itoi M, Fujii K, Tsuchida A, Ooishi H, Kajiyama G (1996) K-ras and p53 mutations in stage I gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct. Cancer 77:452–458PubMedCrossRefGoogle Scholar
  62. 62.
    Wistuba II, Gazdar AF, Rosa I, Albores-Saavedra J (1996) p53 protein overexpression in gallbladder carcinoma and its precursor lesions: an immunohistochemical study. Hum Pathol 27:360–365PubMedCrossRefGoogle Scholar
  63. 63.
    Zhi LZ, Matsubara T, Miura H, Nakamura Y, Hasegawa S, Imazu H, Sakurai Y, Ochiai M, Funabiki T (2001) p53 protein and p53 gene mutations in intrahepatic cholangiocarcinomas and extrahepatic bile duct carcinomas. Tandou (JJ Bil Assoc, in Japanese)Google Scholar
  64. 64.
    Ohashi Y, Watanabe H, Ajioka Y, Hatakeyama K (1995) p53 Immunostaining distinguishes malignant from benign lesions of the gallbladder. Pathol Int 45:58–65CrossRefGoogle Scholar
  65. 65.
    Matsubara T, Funabiki T, Jinno O, Ochiai M, Sakurai Y, Hasegawa S, Imazu H (1999) Analysis of p53 loss of heterozygosity in patients with pancreaticobiliary maljunction by double target fluorescence in situ hybridation. Gekachiryou (in Japanese) 80:617–618Google Scholar
  66. 66.
    Matsubara T, Ishihara S, Miyakawa S, Ochiai M, Funabiki T (2003) Carcinogenic mechanism in pancreaticobiliary maljunction. Naika (in Japanese) 92:1171–1174Google Scholar
  67. 67.
    Yoshida S, Todoroki T, Ichikawa Y, Hanai S, Suzuki H, Fukao K, Miwa M, Uchida K (1995) Mutations of p16INK4/CDKN2 and p15INK4B/MTS2 genes in biliary tract cancers. Cancer Res 55:2756–2760PubMedGoogle Scholar
  68. 68.
    Todani T, Watanabe Y, Toki A (2003) Classification of congenital biliary cystic disease: special reference to type Ic and IVA cysts with primary ductal stricture. J Hepatobiliary Pancreat Surg 10:340–344PubMedCrossRefGoogle Scholar
  69. 69.
    Stain SC, Guthrie CR, Yellin AE, Donovan AJ (1995) Choledochal cyst in the adult. Ann Surg 222:128–123PubMedCrossRefGoogle Scholar
  70. 70.
    Todani T, Watanabe Y, Naruse M, Tabuchi K, Okajima K (1977) Congenital bile duct cysts: Classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst. Am J Surg 134:263–269PubMedCrossRefGoogle Scholar
  71. 71.
    Watanabe Y (2004) Development of bile duct cancer after surgery for pancreaticobiliary maljunction. Shounigeka (in Japanese) 36:495–500Google Scholar
  72. 72.
    Funabiki T, Matsubara T, Ochiai M, Marugami Y, Sakurai Y, Hasegawa S, Imazu H (1997) Surgical strategy for patients with pancreaticobiliary maljunction without choledochal dilatation. Keio J Med 46:169–172PubMedGoogle Scholar
  73. 73.
    Funabiki T, Ochiai M, Amano H, Sugiue K, Fujita S, Fukui H, Matsubara T, Kamei K, Yamaguchi H, Futawatari H, Hasegawa S, Arai K (1987) A new technique of total excision as to the affected bile duct on the congenital choledochal dilatation. Tandou (JJ Bil Assoc, in Japanese) 1:436–442Google Scholar
  74. 74.
    Funabiki T, Sakurai Y, Ochiai M, Marugami Y, Matsubara T, Hasegawa S (1997) End-to-side choledochoduodenostomy: a widely applicable procedure for biliary reconstruction. J Hepatobiliary Pancreat Surg 4:71–77CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Takahiko Funabiki
    • 1
  • Toshiki Matsubara
    • 2
  • Shuichi Miyakawa
    • 3
  • Shin Ishihara
    • 3
  1. 1.Kariya Memorial HospitalFujita Health UniversityToyoakeJapan
  2. 2.Matsubara ClinicIchinomiyaJapan
  3. 3.Department of SurgeryFujita Health UniversityToyoakeJapan

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